The aim of this project is to study mechanisms of immunity, immunoregulation, immune evasion, and immunopathology in schistosomiasis with the ultimate goals of developing an experimental vaccine suitable for human trials and understanding the pathogenesis of disease. In work completed this year, the mechanism by which IL-10 inhibits macrophage-mediated killing of schistosomula was defined and shown to be due to suppression of TNF-alpha synthesis. In addition, IL-10 was shown to synergize with TGF-beta and IL-4 in the inhibition of both larval killing and macrophage production of nitrogen oxide metabolites. An analysis by PCR of cytokine genes expressed in the lungs of mice undergoing schistosome egg granuloma formation revealed a central role for IL-4, IL-2, and IFN-gamma in this process. In related studies, it was discovered that Fcepsilon-positive non-B, non-T cells were the major source of antigen-stimulated IL-4 synthesis in the spleens of infected mice. Finally, schistosome-infected mice were shown to be defective in their ability to clear infections with a recombinant vaccinia construct expressing the GP-160 envelope protein of HIV-1. This decrease in viral resistance correlated with defects in the Th1 cytokine and CTL response to the virus.
